It is known that certain small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution. Gordon, G. S. et al., Proc. Natl. Acad. Sci. USA 82:7419-7423 (1985). However, the efficacy of absorption is typically low and variable and therapeutically important peptides of larger molecular size, such as insulin, are not absorbed to any appreciable degree. Hirai et al., Diabetes 27:296-299 (1978).
A number of researchers have attempted to increase the delivery of polypeptides with detergents. For example, Gordon, G. S. et al., Proc. Natl. Acad. Sci. USA 82:7419-7423 (1985), report that the nasal absorption of insulin can be increased by hydrophobic bile salts.
Longenecker, J. P. et al., J. Pharm. Sci. 76:351-355 (1987), disclose that sodium taurodihydrofusidate is an effective increaser of mucosal permeation of drugs, in particular, insulin.
Morimoto, K. et al., J. Pharm. Pharmacol. 37:134-136 (1984), disclose that the nasal absorption of insulin and calcitonin can be increased with polyacrylic acid gel.
See also Moses, A. C. et al., Diabetes 32:1040-1047 (1983), who disclose the administration of insulin as part of an insulin-bile salt aerosol; and Aungst, B. J. et al., J. Pharm. Exp. Ther. 244:23-27 (1988), who compared the nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter.
Maitani, Y. et al., Drug Design Del. 1:65-70 (1986), disclose the intranasal administration of .beta.-interferon with and without surfactants (non-ionic, anionic and amphoteric). When no surfactant was used, .beta.-interferon was not absorbed in rabbits. Sodium glycocholate was the most effective in enhancing the absorption of interferon following nasal administration. However, the total absorption of .beta.-interferon with sodium glycocholate was 2.2% of the total absorption by intravenous administration.
Other detergents that have been employed to increase the uptake of polypeptides by mucosal tissue include saponins. Saponins occur widely in plant species (over 400) and exhibit a range of biological properties, some of which are beneficial and some deleterious. When agitated in water, they form a soapy lather and it is this characteristic that gives the group its name. Other properties generally ascribed to saponins include, for example, hemolytic activity, cholesterol-binding properties and bitterness. For a review of the chemistry and a biological significance of saponins, reference is made to Price, K. R. et al., CRC Crit. Rev. Food Sci. Nutr. 26:27 (1987).
Solutions of saponin have been employed to increase the delivery of polypeptides across mucosal membranes. For example, Pillion, D. J. et al., Invest. Opthal. Vis. Sci. 32:3021-27 (1991) disclose that administration of insulin in eyedrops containing unpurified saponin from Gypsophilla as a 1% solution causes a rapid and reproducible reduction in the blood levels of D-glucose in rats. Insulin eyedrops lacking saponin were ineffective. Japanese Abstract No. JP 62126135 (1987) discloses the nasal administration of growth hormone releasing factor employing a saponin having a steroidal or triterpene structure. See also, Chiou, G. C. Y. et al., J. Pharm. Sci. 78:815.818 (1989); and Chiou G. C. Y. et al., J. Ocul. Pharm. 5:81-91 (1989) who disclose the systemic delivery of insulin by administration as part of eyedrops containing saponin (obtained from Sigma Chemical Company). See also, Chiou, G. C. Y. et al., Diabetes Care 11:750-51 (1988) (source of saponin undisclosed). See also, Hirari, S. et al., Int. J. Pharm. 9:173-84 (1981) and Hirari, S. et al., Int. J. Pharm. 9:165-72 (1989), who disclose the nasal administration of insulin in rats with a solution comprising saponin (source not disclosed other than that the saponin was obtained from the Wako Pure Chemical Ind., Lid, Osaka, Japan).
While surfactants hold great promise for enhancing the uptake of drugs across mucosal membranes, a major drawback is that they cause irritation. Thus, the long-term use of pharmaceutical compositions comprising a surfactant cannot be possible. However, for acute therapies, local effects are less important because the mucosal membrane can easily repair itself. Long-term local toxicity effects are even more important when increasers are used to increase nasal membrane permeability. Chronic erosion of the mucous membrane by certain surfactants such as polyoxyethylene-9 lauryl ether could result in inflammation, hyperplasia, metaplasia and deterioration of normal nasal functions. Lee, W. A. and Longenecker, J. P., BioPharm. 30-37 (1988).
Literature reports indicate that biosalts break down mucous membrane structure (Martin, G. P. and Marriot, C., J. Pharm. Pharmacol. 31:754 (1981), accelerate phospholipid and protein release from membranes (Whitmore, D. A. et al., J. Pharm. Pharmacol. 31:277 (1979), and damage intestinal mucosa (Kimura, T. et al., J. Nut. Sci. Vitaminol. 28:483 (1982). Chronic erosion also exposes nasal circulation to a constant stream of airborne bacteria and related toxins. Lee, W. A. and Longenecker, J. P., Biopharm. 30-37 (1988). Thus, a need continues to exist for the development of new surfactants that increase the delivery of drugs across mucosal membranes without causing irritation.